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Risk Factors, Surveillance Strategies, and Treatment Options for HCC

Annual Report of HepatomaKeelung CGMH

Risk Factors, Surveillance Strategies, and Treatment Options for Hepatocellular Carcinoma



662,000 deaths from liver cancer yearly worldwide

Leading cause of death among male malignancies in

Taiwan (2007 )

World Health Organization. Available at: http://www.who.int/whosis/en/. Accessed October 6, 2008. American Cancer Society. Cancer facts & figures 2008. Atlanta: American Cancer Society; 2008.



Sangiovanni A, et al. Gastroenterology. 2004;126:1005-1014.

Cause of Death, n (%) All Patients HCC-Free Patients

Patients Who Developed HCC

Tumor progression 54 (36) 0 (0) 54 (66)

Nonliver-related conditions 28 (19) 23 (34) 5 (6)

Liver failure 25 (17) 18 (27) 7 (9)

Gastrointestinal hemorrhage 21 (14) 13 (19) 8 (10)

OLT-related complications 2 (1) 0 (0) 2 (2)

Unknown 19 (13) 13 (19) 6 (7)

Total 149 (100) 67 (100) 82 (100)

1987-2001: Causes of Death in Patients With Compensated Cirrhosis HCC-free outpatients with compensated cirrhosis followed

for 148 months with periodic ultrasound in Italy (N = 417)



Treatment for HCC Often Suboptimal Proportion of patients receiving potentially curative therapy

N = 2963 from 1992-1999 in USA

– 34.0% of patients with single lesions

– 34.0% of patients with lesions < 3 cm

– 19.2% of patients with lesions > 10 cm

– 4.9% of patients with metastatic disease

11.5% of patients ideal for transplantation received it

12.9% of patients ideal for surgical resection received it

El-Serag HB, et al. J Hepatol. 2006;44:158-166.



HCC Surveillance



Is Surveillance “Worthwhile”?

How do we define “worthwhile”?

– Improvement in survival of 3 months[1]

Surveillance considered cost-effective if it achieves this 3-month improvement in survival at a cost of < $50,000 per life-year saved[2]

1. Naimark D, et al. J Gen Intern Med. 1994;9:702-707. 2. Laupacis A, et al. CMAJ. 1992;146:473-481.



Surveillance for HCC

Objective

– To reduce mortality from HCC

A single randomized controlled trial of 18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled

– Surveillance group offered US and AFP every 6 months (n = 9373)

– Control group received no surveillance (n = 9443)

– surveillance hepatitis B carriers with semiannual AFP and US reduces HCC-related mortality by 37%

Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422.



Identification of At-Risk Population for HCC Surveillance What level of risk makes surveillance worthwhile?

– Incidence

According to randomized controlled trials

– Hepatitis B: 0.28% per year[1]

According to cost-efficacy analyses

– Hepatitis B: 0.2% per year[3]

– Non-hepatitis B cirrhosis: > 1.4% per year[4]

1. Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422. 2. Sarasin FP, et al. Am J Med. 1996;101:422-434. 3. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file. 4. Arguedas MR, et al. Am J Gastroenterol. 2003;98:679-690.



The Benefit of Surveillance

For HCC incidence of 1.5%/ year, → survival increases for 3 months after surveillance

For HCC incidence of 6%/year → increase of 9 months.

Cost-effective -when the incidence of HCC > 1.4%. .

Recommendation :Surveillance for risk of HCC >=1.5%/year

Sarasin, FP, Am J Med 1996;101:422-434. Arguedas Am J Gastroenterol 2003;98679-690.

Lin OS, Aliment Pharmacol Ther 2004;19:1159-1172



Hepatitis B Carriers Suitable for HCC Surveillance Hepatitis B carriers[1-4]

– Asian males > ~ 40 years (incidence ~ 0.4% to 0.6% per year)

– Asian females > ~ 50 years (incidence ~ 0.2% per year)

– Africans older than 20 years of age (incidence unknown but likely > 0.2% per year)

– Cirrhosis (HCC incidence: 3% to 5%/year)

– Family history of HCC: mainly Asian and African

Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol. 2003;39(suppl 1):S50-S58.



Factors Affecting HCC Risk

Active disease

– Elevated ALT

Persistently elevated AFP

Low platelet count

HBV DNA level

Histologic changes

– Dysplasia

– Geographic morphologic changes

– PCNA (Proliferating cell nuclear antigen) positive

Use of TIPS (?)

Beasley RP, et al. Lancet. 1981;2:1129-1133. Degos F, et al. Gut. 2000;47:131-136. Oka H, et al. Hepatology. 1994;19:61-66. Zhang JY, et al. Am J Trop Med Hyg. 1998;59:947-951. Colombo M, et al. N Engl J Med. 1991; 325:675-680.Ganne-Carrie N, et al. Hepatology. 1996;23:1112-1118. Lee RG, et al. Hepatology. 1997;26:1415-1422. Chen CJ, et al. JAMA. 2006;295:65-73.



Screening and Surveillance Methodology:

Serologic Tests and Radiology

Current Serologic Screening Tests Are Insufficiently Sensitive



Sensitivity of AFP Surveillance for HCC

Study Sensitivity, %

Case-control studies

Trevisani 2001 60

Surveillance studies

Tanaka 1990 64

Pateron 1994 50

Borzio 1995 47

Sherman 1995 64

Solmi 1996 54

Zoli 1996 62

McMahon 2000 97

Bolondi 2001 41

Tong 2001 59Trevisani F, et al. J Hepatol. 2001;34:570-575. Tanaka S, et al. Cancer. 199015;66:2210-2214. Pateron D, et al. J Hepatol. 1994;20:65-71. Borzio M, et al. Gastroenterology. 1995;108:812-817. Sherman M, et al. Hepatology. 1995;22:432-438. Solmi L, et al. Am J Gastroenterol. 1996;91:1189-1194. Zoli M, et al. Cancer. 1996;78:977-985. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559.



Specificity of AFP Surveillance for HCC

*5% prevalence of HCC.

Study Specificity, % PPV, %

Case-control studies

Trevisani 2001 91 25*

Surveillance studies

Pateron 1994 86 33

Sherman 1995 91 9

McMahon 2000 95 31

Bolondi 2001 82 46

Tong 2001 91 11

Trevisani F, et al. J Hepatol. 2001;34:570-575. Pateron D, et al. J Hepatol. 1994;20:65-71. Sherman M, et al. Hepatology. 1995;22:432-438. McMahon BJ, et al. Hepatology. 2000;32:842-846. Bolondi L, et al. Gut. 2001;48:251-259. Tong MJ, et al. J Gastroenterol Hepatol. 2001;16:553-559.



Other Tumor Markers Des-gamma-carboxy prothrombin (DGCP), also known

as Prothrombin Induced by Vitamin K Absence II (PIVKA) 40 mAU/ml≧

The ratio of glycosylated AFP L3 (Lectin fraction)

to total AFP>15%, alpha fucosidase and glypican



HCC Surveillance by Ultrasound

Performance characteristics of ultrasound as a screening test

Performance Characteristic, %

Cohort 1Years 1-5

Cohort 1Years 6-8

Cohort 2Years 1-3

Sensitivity 79 87 80

Specificity 94 87 91

PPV 15 13 14

NPV 98 100 100

Collier J and Sherman M. AASLD 1995. Morris Sherman, MB BCh, PhD, FRCP(C). Data on file.



HCC Surveillance by CT Scan

No evidence to support the use of CT scanning for routine HCC surveillance

– PPV and NPV unknown

– Accurate use of CT requires 4-phase contrast CT

– Radiation exposure is significant

– In the absence of contrast CT, false-positive rate very high

– Cannot distinguish small HCC from dysplastic nodules or arterialized cirrhotic nodules

– Flow abnormalities create diagnostic difficulty



Standard angiography and CTAP angiography

Contrast enhanced ultrasound (CEUS) could also be used for this non-invasive diagnosis.

Other radiological tests. In particular lipiodol angiography is not sensitive for small HCC.

Standard angiography and CTAP( arterioportal angiography) should not be routinely performed.



Surveillance Interval: 6 vs 12 Months

Trevisani et al[1]

– Survival similar with 6-month vs 12-month surveillance

Santagostino et al[2]

– Rate of detection of single nodules (vs multinodular HCC) similar with 6-month vs 12-month surveillance

Kim et al[3]

– Survival improved with 6-month vs 12-month surveillance

1. Trevisani F, et al. Am J Gastroenterol. 2002;97:734-744. 2. Santagostino E, et al. Blood. 2003;102:78-82. 3. Kim DY, et al. AASLD 2007. Abstract 368.



AASLD and NCCN Surveillance Guidelines

AASLD Guidelines

Surveillance recommended in at-risk groups

– Specific hepatitis B carriers

– Nonhepatitis B cirrhosis

US preferred surveillance tool

– AFP alone should not be used unless US unavailable

Patients should be screened at 6- to 12-month intervals

NCCN Guidelines National Comprehensive Cancer Network

(21家世界頂級癌症中心組成的非營利性學術聯盟 )

US and AFP, AP, and albumin for surveillance in high-risk patients

– Every 3-6 months

Continue screening every 3 months in those with high AFP but no evidence on imaging

Bruix J, et al. Hepatology. 2005;42:1208-1236. National Comprehensive Cancer Network.Available at: http://www.nccn.org/professionals/physician_gls/PDF/hepatobiliary.pdf. Accessed October 14, 2008.



Japan Society of Hepatology (JSH) - 2007Consensus-Based Clinical Practice Manual



Population at Risk for HCC



Summary

At-risk patients should be screened for HCC

Ultrasound surveillance is preferable

– AFP increased the detection rate

Surveillance should take place at 3-6-month intervals for high risk patients

– Evidence for better survival than 12-month intervals



Diagnosis of Hepatoma



EASL conference on HCC diagnosisTumors>2 cm

The diagnosis of HCC can be made without biopsy :

In Cirrhotic patients who have a mass> 2 cm that shows characteristic arterial vascularization on two imaging modalities,

- Triphasic CT scan and MRI.

The positive predictive value of the clinical and radiological findings exceeds 95%



Tumors 1-2 cm in diameter

Lesions between 1-2 cm in a cirrhotic liver have a high likelihood of being HCC.

These lesions should be biopsied irrespective of their vascular profile

Biopsy of small lesions (2 cm) may not be reliable

Needle placement may be difficult

D.D. Dysplasia and well-differentiated HCC



Lesions Less Than 1 cm in Diameter

Low likelihood of being HCC

Malignancy is even less likely if they do not show contrast uptake on dynamic imaging

Even if CT or MRI show tiny nodules with arterial vascularization. They may not correspond to HCC foci.

Need to be followed-up every 3-6 months. (level III).

Lack of growth over a period of more than 2 years suggests that the lesion is not HCC



Recommendations

if the vascular profile on imaging is not characteristic or if the nodule is detected in a non-cirrhotic liver,

-- Biopsy should be performed (level II).

Biopsies of small lesions should be evaluated by expert pathologists. If the biopsy is negative for HCC patients should be followed by ultrasound or CT scanning at 3-6 monthly intervals

If the lesion enlarges but remains atypical for HCC a repeat biopsy is recommended (level III).



Diagnosis in High Risk Patients



Atypical Image on Dynamic CT/MRI(JSH)

When a lesion is intensely enhanced in the early arterial phase and becomes low-attenuation in the equilibrium phase,,

R/O FNH and A-P shunt,

Uptake by Kupffer cells is investigated by

1.SPIO (superparamagnetic iron oxide -enhanced MRI )

2.Sonazoid-enhanced ultrasonography.

When high SPIO-enhanced MRI signals or a defect in the

Kupffer phase of Sonazoid-enhanced ultrasonography

are confirmed, the lesion is diagnosed as HCC



Tumor Staging



Currently there are 3 staging systems for HCC:

(1) TNM staging as tumor spreading staging,

(2) liver function staging

(3) systems integrating (1) and (2). For TNM staging,



Staging System

UICC( international union against cancer) or AJCC (American joint

committee on cancer) classification is used internationally (2005)

These are thought inappropriate because the cut-off tumor size is set to 5 cm (JSH)

Portal microinvasion and intrahepatic metastasis occurs in 27% and 10% of tumors with a tumor size of 2 cm or more



TNM Stage by LCSG



Functional staging & TNM



Barcelona-Clinic- Liver-Cancer (BCLC) staging system



Cancer of the Liver Italian Program (CLIP)

The CLIP score retrospective evaluation of 435 Italian patients with HCC diagnosed from 1990 to 1992.



Japan Integrated Staging Score



The Treatment of HCC



Liver Transplantation for HCC:Milan Criteria (Stage 1 and 2)

+Absence of macroscopic vascular invasion,

absence of extrahepatic spread

Single tumor, not > 5 cm Up to 3 tumors, none > 3 cm

Mazzaferro V, et al. N Engl J Med. 1996;334:693-699.



Treatment: Chemoembolization

Normal liver gets 75% of blood supply from portal vein and 25% of blood supply from hepatic artery

Tumor receives most of its blood supply from the hepatic artery

Injection into the hepatic artery spares most of the normal liver

Embolization of the hepatic artery prevents systemic absorption of chemotherapy agents and induces ischemic necrosis of tumor

Tumor

Liver

Portal vein

Hepaticartery

Catheter placement forchemoembolization



Chemoembolization: Randomized Trials (Nearly Identical Techniques)

TechniqueSurvival, %

Year 1 Year 2 Year 3

TACE 57 31 26

Supportive care 32 11 3

TechniqueSurvival, %

Year 1 Year 2

TACE 82 63

Supportive care 63 27

Llovet et al[2]: N = 112 with unresectable HCC, 80% to 90% HCV positive, 5-cm tumors (~ 70% multifocal)

Lo et al[1]: N = 80 with newly diagnosed unresectable HCC, 80% HBV positive, 7-cm tumors (60% multifocal)

1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.



Intra-arterial Locoregional Therapy

Established

– TACE

– Radioembolization: yttrium-90 radioactive microspheres

Undergoing clinical trials

– Drug-eluting beads



Radioembolization: Use of intra-arterially delivered yttrium-90 microspheres emitting high-dose radiation for the treatment of liver tumors

Yttrium-90 microspheres

– Average diameter: 20-30 µm

– 100% pure beta emitter (0.9367 MeV)

– Physical half-life: 64.2 hours

– Irradiates tissue with average path length of 2.5 mm (maximum: 11 mm)

Intra-arterial Radioembolization With Yttrium-90: Rationale and History

Murthy R, et al. Biomed Imaging Interv J. 2006;3:e43.



Clinical Response to Yttrium-90 MicrospheresOutcome Dancey

et al[1]

(N = 20)

Carr et al[2]

(N = 65)Geschwind

et al[3]

(N = 80)

Salem et al[4]

(N = 43)

Response rate, % 39 47

Median survival 378 days(> 104 Gy)

Okuda stage I 649 days 628 days 24.4 mos

Okuda stage II 302 days 384 days 12.5 mos

1. Dancey JE, et al. J Nucl Med. 2000;41:1673-1681.2. Carr BI. Liver Transpl. 2004;10(2 suppl 1):S107-S110.3. Geschwind JF, et al. Gastroenterology. 2004;127(5 suppl 1):S194-S205.4. Salem R, et al. J Vasc Interv Radiol. 2005;16:1627-1639.



27 patients with Child-Pugh A stage disease

Response rate (assessed by CT) at 6 months: 75%

1- and 2-year survival rates: 92% and 89%

– Median follow-up: 28 months

Varela M, et al. J Hepatol. 2007;46:474-481.

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TACE With Doxorubicin-Eluting Beads: Efficacy and Pharmacokinetics



Targeted Molecular TherapiesMechanisms of Action (cont’d) Multiple pathways

– Sorafenib

– RAF/MEK/ERK signaling

– VEGFR-2

– PDGF-β

– Brivanib

– VEGFR-2

– FGFR-1 kinase

– Pazopanib

– VEGFR-1, -2, -3

– PDGF-α, -β

– c-KIT



Sorafenib in Advanced HCC: The SHARP Trial Entry criteria

– Advanced HCC

– Not eligible for or failed surgical or locoregional therapies

– Child-Pugh class A disease

– At least 1 untreated target lesion

– Exclusions

– Previous chemotherapy

– Previous molecularly targeted therapy

Llovet JM, et al. N Engl J Med. 2008;359:378-390.



Llovet JM, et al. Sorafenib in advanced hepatocellular carcinoma. N Engl J Med. 2008;359:378-390. © 2008, Massachusetts Medical Society. All rights reserved.

Median OSSorafenib: 10.7 mos

Placebo: 7.9 mosMedian TTSP

Sorafenib: 4.1 mosPlacebo: 4.9 mos

Median TTRPSorafenib: 5.5 mosPlacebo: 2.8 mos

The SHARP Trial: OS and Time to Progression

Months Since Randomization

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Staging Strategy and Treatment for Patients With HCC

Liver transplant PEI/RF

Curative treatments

TACE

HCC

Single

Increased Associateddiseases

Normal No Yes No Yes

Terminalstage

PST 0-2, Child-Pugh A-B

Multinodular, PST 0

Portal invasion, N1, M1

Sorafenib

Portal pressure/bilirubin

3 nodules ≤ 3 cm

Intermediate stage

PST > 2, Child-Pugh C

Very early stageSingle < 2 cm

Early stageSingle or 3 nodules

≤ 3 cm, PST 0

Advanced stagePortal invasion,

N1, M1, PST 1-2

PST 0, Child-Pugh A

Resection

Symptomatic (unless LT)

Llovet JM, et al. J Natl Cancer Inst. 2008;100:698-711.Bruix J, et al. Hepatology. 2005;42:1208-1236.

RCTs (50%) Median survival: 11-20 mos



Treatment Algorithm for Hepatoma



Annual Report of Hepatoma 2008



Annual Report of Hepatoma Patients 2008

A total of 126 patients were recruited from cancer registration, pathology report

Female : Male = 38:88

The age aged from 23 to 91 years old

Mean ± SD = 65.46 ± 13.28



child

84 66.7 66.7 66.727 21.4 21.4 88.115 11.9 11.9 100.0

126 100.0 100.0

ABCTotal

ValidFrequency Percent Valid Percent

CumulativePercent



•HACE 33.3%•HACE 33.3%

•OP13.5%•OP13.5%

•Conservative13.5%•Conservative13.5%

•Transfer 5.6%•Transfer 5.6%

•RFA 24.6%•RFA 24.6%

•C/T 7.9%•C/T 7.9%



Pathology

Pathology was obtained in 91 among 126 patients

9 were not diagnostic : Negative 1, Fatty liver 1 , cirrhosis 6, chronic active hepatitis 1

Grade I 2

Grade II 31

Grade III 30

Grade IV 2

HCC without grading 13

Carcinoma 4



Diagnosis of Hepatoma The most sensitive modality capable of objectively

depicting the early carcinogenesis process among currently available imaging systems is

(1) CTAP

(2) CTHA (hepatic arteriography)

(3) contrast-enhanced ultrasonography(US)

(4) SPIO-MRI [24, 25]



The Risk of HCC in Patients with Chronic Hepatitis C

In cirrhotic patients, the incidence 2%-8% / year.

Anti-HCV-positive conferred a 20-fold increased risk of HCC (12,008 men)

Surveillance for cirrhosis or bridging fibrosis or transition to cirrhosis.



Staging system CLIP scores or BCLC stages are used in Europe and North America as

staging systems.

the BCLC stage is basically a treatment selection system for deciding on a therapeutic strategy,

CLIP and JIS scores are prognostic prediction stagings.

The CLIP score and BCLC stage tend to detect relatively large HCCs,

JIS score is most useful for countries where many

small liver cancers are detected.

28 Bruix J, Sherman M, Llovet JM, et al: Clinical management of hepatocellular carcinoma. Conclusions of the Barcelona-2000 EASL Conference. J Hepatol 2001; 35: 421–430.

29 Llovet JM, Bru C, Bruix J: Prognosis of hepatocellular carcinoma: the BCLC staging classification. Semin Liver Dis 1999; 19: 329–338



Interferon & Lamivudine

No convincing evidence that interferon treatment of chronic hepatitis B reduces the incidence of HCC.

A single RCT suggests that lamivudine treatment reduce the incidence of HCC

in HBV-related cirrhosis ??



Hepatitis C treated with interferon

A single RCT in Japan suggested that

the incidence of HCC was reduced in both responders and non-responders

In a meta-analysis, benefit is mainly seen in sustained virological responders, and

the effect was small.



Recommendations

17. Local ablation is safe and effective therapy for

patients who cannot undergo resection, or as a bridge to transplantation (level II).

18. Alcohol injection and radiofrequency are

equally effective for tumors <2 cm. However, the

necrotic effect of radiofrequency is more predictable in all tumor sizes and in addition, its efficacy is clearly superior to that of alcohol injection in larger tumors (level I).



Surgical Recommendations

Recommendations

Patients who have a single lesion can be offered surgical resection if they are non-cirrhotic or have cirrhosis but still have well preserved liver function,

normal bilirubin and

hepatic vein pressure gradient <10 mmHg (level II).

Pre or post-resection adjuvant therapy is not

recommended (level II)



Largest Prospective Study of TACE for Unresectable HCC to Date N = 8510 patients

Primary endpoint: OS

Multivariate analysis conducted of factors affecting survival

OS

– Year 1: 82%; Year 3: 47%; Year 5: 26%; Year 7: 16%

– OS better with lesser degree of liver damage

Factors affecting survival

– Child-Pugh stage

– TNM stage (OS better with stage I, increasingly worse progressing toward stage IV)

– Alpha-fetoprotein level

Takayasu K, et al. Gastroenterology. 2006;131:461-469.



Embolization: Summary

Well-performed comparative studies between chemoembolization, radioembolization, and bland embolization needed

Chemoembolization has longest “track record” and data suggest survival advantage

Radioembolization data rapidly accumulating

– Advantages include lack of induction of ischemia, outpatient procedure without postembolization syndrome

Bland embolization

– Response demonstrable but not clear if benefits in cost; questionable benefits in toxicity outweigh likely decreased response

– Potential role (especially niche role, such as in patients with poor hepatic function or in combination with ablative therapy) remains to be proven



Transarterial Embolization and Chemoembolization Recommendations

19. TACE is recommended as first line non-curative

therapy for non-surgical patients with large/multifocal

HCC who do not have vascular invasion or extrahepatic

spread (level I).

20. Tamoxifen, antiandrogens, octreotide or hepatic

artery ligation/embolization are not recommended

(level I).



Chemoembolization: Predictors of Survival Lo et al[1]

– Absence of presenting symptoms (ECOG PS < 2)

– Absence of portal vein obstruction

– Tumor size (≤ vs > 5 cm)

– Okuda stage (I vs II)

Llovet et al[2]

– Absence of constitutional syndrome (ECOG PS < 2)

– Low serum bilirubin

– Treatment response (modified WHO criteria, > 6 months)

1. Lo CM, et al. Hepatology. 2002;35:1164-1171.2. Llovet JM, et al. Lancet. 2002;359:1734-1739.



Targeted Molecular Therapies:Mechanisms of Action VEGF antagonists

– Cediranib

– ABT-869

NF-κB antagonists

– Perifosine

Proteasome inhibitors

– Bortezomib



32 patients with HCC and PVT

Median OS: 10 months

Child-Pugh score: best prognostic factor (ie, most strongly related to survival)

30-day mortality: 0%

No evidence of TACE-related hepatic infarction or acute liver failure

Safety & Efficacy of TACE in Patients With Unresectable HCC & PVT

Georgiades CS, et al. J Vasc Interv Radiol. 2005;16:1653-1659.



Diagnosis of HCC

AFP > 200 & radiological appearance suggestive of HCC (large and/or mutifocal disease with arterial hypervascularity), Biopsy is not essential.

If the imaging appearances are atypical. Tumor biospy should be considered.



Selecting an HCC Surveillance Interval

Dependent on

– Tumor growth rate

– Prognosis of HCC at different sizes

– < 1-2 cm

– 2-3 cm

– > 3 cm

– Ideal surveillance interval unknown

– Tumor growth rates suggest every 4-12 months

Does not depend on degree of risk



Targeted Molecular Therapies:Mechanisms of Action (cont’d) EGFR tyrosine kinase inhibitors

– Lapatinib

– Sunitinib

– Erlotinib

TRAIL receptor antibodies

– Mapatumumab

BCR-ABL inhibitors

– Dasatinib



CLIP score - prognostic system for patients with HCC



Zhang BH, et al. J Cancer Res Clin Oncol. 2004;130:417-422.

Outcome of HCC Surveillance

18,816 people with HBV infection or history of chronic hepatitis in urban Shanghai, China enrolled

– Surveillance group offered US and AFP every 6 months (n = 9373)

– Control group received no surveillance (n = 9443)

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Phase II study: N = 108 (37 with PVT, 71 without PVT)

Stratified by toxicity: Child-Pugh score (in cirrhotics), dose, location of PVT

Median dose: 134 Gy

Partial response rate: 42% (WHO), 70% (EASL)

Adverse event rate highest in patients with main PVT and cirrhosis

Median survival, main PVT: 260 days

– Branch PVT: 370 days

– No PVT: 460 days

Yttrium-90 Radiotherapy for HCC Patients With and Without PVT

Kulik LM, et al. Hepatology. 2008;47:5-7.



Absolute contraindications

– Child-Pugh class C disease

– Poor performance status (ECOG PS > 2)

Relative contraindication

– Extrahepatic disease (benefit unclear)

Former contraindication

– PVT

– Minimize embolization and be more selective

Chemoembolization: Ineligibility Criteria



Incidence of HCC in Risk Groups

Subgroup Incidence per Year (%)

All hepatitis B carriers > 40 yrs of age 0.2

Cirrhotic hepatitis B carriers 3-8

Hepatitis C cirrhosis 3-5

Stage 4 primary biliary cirrhosis 3-5

Alcoholic cirrhosis ?

Genetic hemochromatosis ?

Nonalcoholic steatohepatitis ?

Beasley RP, et al. Lancet. 1981;2:1129-1133. Koike K, et al. Oncology. 2002;62(suppl 1):29-37. Beasley RP. Hepatology. 1982;2(suppl):21S-26S. Fattovich G, et al. Gut. 1991;32:294-298. Manno M, et al. Gastroenterology. 2004;127:756-763. Hsu YS, et al. Hepatology. 2002;35:1522-1527. Fattovich G. J Hepatol 2003;39(suppl 1):S50-S58. Fattovich G, et al. Gastroenterology. 1997;112:463-472. Niederau C, et al. Hepatology. 1998;28:1687-1695. Niederau C, et al. N Engl J Med. 1996;334:1422-1427. Degos F, et al. Gut. 2000;47:131-136. Caballeria L, et al. Am J Gastroenterol. 2001;96:1160-1163.

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